IL2RA+VSIG4+ tumor-associated macrophage is a key subpopulation of the immunosuppressive microenvironment in anaplastic thyroid cancer
IL2RA+VSIG4+ tumor-associated macrophage is a key subpopulation of the immunosuppressive microenvironment in anaplastic thyroid cancer
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IL2RA VSIG4 肿瘤相关巨噬细胞是甲状腺未分化癌免疫抑制微环境的关键亚群
DOI：
10.1016/j.bbadis.2022.166591
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Minghua Ge
中科院分区：
文献类型：
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作者：
Zongfu Pan;Lisha Bao;Xixuan Lu;Xiaoping Hu;Lu Li;Jinming Chen;Tiefeng Jin;Yiwen Zhang;Zhuo Tan;Ping Huang;Minghua Ge
肿瘤相关巨噬细胞的广泛浸润与甲状腺未分化癌（ATC）预后不良有关。然而，ATC相关巨噬细胞（ATAMs）在ATC中的异质性和特征仍然很不清楚。我们结合单细胞RNA测序分析和基因表达微阵列数据集来评估ATAM的分子特征。与正常甲状腺相关巨噬细胞（NTAMs）相比，778个差异表达基因（DEG）在ATAMs中发生了显著变化。这些DEG与氧化磷酸化（M2表型）和吞噬作用（M1表型）相关。此外，ATAM高度表达与血管生成、纤维化、金属蛋白酶活性和转移相关的促肿瘤基因。值得注意的是，我们鉴定了一个ATC特异性子集，IL2RA+VSIG4+ ATAM，共表达M1和M2标志物。IL 2RA +VSIG4+ATAMs的浸润与BRAF和RAS信号密切相关，其高浸润与甲状腺癌患者的良好预后相关。IL 2 RA + VSIG 4 + ATAM与增加的肿瘤浸润淋巴细胞（B细胞、CD8+T细胞、T淋巴细胞）相关。IL2RA+VSIG4+ ATAM通过免疫检查点（例如LGALS9_HAVCR 2）、细胞因子（例如CXCL 10_CXCR 3）和受体（例如CSF1R_CSF1）与CD8+T细胞和T细胞相互作用，从而形成免疫抑制微环境。多重免疫组织化学染色和共培养实验证实ATC癌细胞能够诱导IL 2RA + VSIG 4 + ATAM的极化。此外，我们还鉴定了几个新的ATC特异性免疫检查点基因，包括免疫抑制分子VSIG 4，LAIR 1和LILRB 2。VSIG 4的表达还与肿瘤浸润淋巴细胞（B细胞、CD8+T细胞、TcB）显著相关。总之，我们的研究揭示了一个具有双功能表型的ATC特异性ATAM亚群，这为描述ATC相关巨噬细胞的分子特征提供了全面的见解。
Extensive infiltration of tumor-associated macrophages was correlated poor prognosis in anaplastic thyroid cancer (ATC). However, the heterogeneity and characteristics of the ATC-associated macrophages (ATAMs) in ATC remain far from clear. We combined single-cell RNA-sequencing analysis and gene expression microarray datasets to assess the molecular signature of ATAMs. Compared with normal thyroid-associated macrophages (NTAMs), 778 differentially expressed genes (DEGs) significantly changed in ATAMs compared with NTAMs. These DEGs were correlated with oxidative phosphorylation (M2 phenotype) and phagocytosis (M1 phenotype). Moreover, ATAMs highly expressed pro-tumor genes associated with angiogenesis, fibrosis, metalloprotease activity, and metastasis. Notably, we identified one ATC-specific subset, IL2RA+VSIG4+ATAMs, co-expressed M1 and M2 markers. The infiltration of IL2RA+VSIG4+ATAMs showed strong correlation with BRAF and RAS signaling, and its high infiltration was associated with favorable prognosis in thyroid-cancer patients. IL2RA+VSIG4+ATAMs were associated with increased tumor-infiltrating lymphocytes (B cells, CD8+T cells, Tregs). IL2RA+VSIG4+ATAMs interacted with CD8+T cells and Tregs through immune checkpoints (such as LGALS9_HAVCR2), cytokines (such as CXCL10_CXCR3), and receptors (such as CSF1R_CSF1), thereby forming an immunosuppressive microenvironment. Multiplex immunohistochemistry staining and coculture experiment confirmed that ATC cancer cells were able to induce the polarization of IL2RA+VSIG4+ATAMs. Besides, we identified several novel ATC-specific immune checkpoint genes including the immunosuppressive molecule VSIG4, LAIR1, and LILRB2. Expression of VSIG4 was also significantly correlated with tumor-infiltrating lymphocytes (B cells, CD8+T cells, Tregs). In conclusion, our study revealed an ATC-specific ATAM subset with bifunctional phenotype, which provided a comprehensive insight to delineate the molecular characteristics of ATC-associated macrophages.